Epigenetic modifications, such as DNA methylation and covalent histone modifications, involve heritable changes in gene expression without changing the underlying DNA sequence. Exposure of the developing germline to these environmental factors, such as diet, drugs, chemicals and stress, can elicit epigenetic changes and contribute to inherited disease in offspring. Work in mice has shown that a specific epigenetic regulator, Polycomb Repressive Complex 2 (PRC2), is required in oocytes for growth and development in offspring. PRC2 catalyses tri-methylation of lysine 27 in histone 3 (H3K27me3), which inhibits gene expression. H3K27me3 is often found in promoter regions of developmentally important genes thereby repressing target genes and regulating cell differentiation in multiple tissues, including brain, bone and germ cells. In humans, de novo germline mutations in the essential PRC2 encoding genes Embryonic Ectoderm Development (EED) or Enhancer of Zeste 2 (EZH2) result in Cohen-Gibson and Weaver syndromes, respectively, which are characterised by fetal overgrowth, skeletal defects and reduced learning capacity in children.
We have developed a model that deletes EED only in growing oocytes in mice, enabling the study of epigenetic inheritance through the production of genetically identical offspring from eggs that have differences in EED-dependent epigenetic programming. This model has demonstrated that loss of EED in the female germline results in fetal overgrowth and skeletal defects, reminiscent of Cohen-Gibson Syndrome in humans. The current study aims to characterise the impacts of the loss of EED in mouse oocytes on offspring learning capacity, brain development and behaviour. The outcomes will provide the first insights into the role of EED, and the epigenetic mechanisms it modulates, for regulating heritable changes in brain development and behaviour. Understanding this and similar epigenetic mechanisms is critical for determining how environmental factors in parents, such as drug or dietary exposures, may affect learning and behavioural outcomes in offspring.